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Test Code AFTDP Inherited Frontotemporal Dementia and Amyotrophic Lateral Sclerosis Gene Panel, Varies


Ordering Guidance


First tier testing for a diagnosis of dementia or amyotrophic lateral sclerosis is C9ORF / C9orf72, Hexanucleotide Repeat, Molecular Analysis, Varies, which is included with this test but is also available separately.

 

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

 

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.


Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Neurology Patient Information

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.

Secondary ID

617493

Useful For

Establishing a molecular diagnosis for patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS)

 

Identifying variants within genes known to be associated with FTD and/or ALS, allowing for predictive testing of at-risk family members

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

FTD and ALS Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Frontotemporal dementia (FTD) is a progressive neurodegenerative syndrome that affects the frontal and temporal cerebral cortices. Clinical presentation is variable and includes changes in behavior, difficulties with language, rigidity, palsy, and saccadic (rapid) eye movement. Symptoms generally begin between 40 and 60 years of age, with a mean age of onset at approximately 45 years. They typically last between 5 and 10 years, progressing to severe dementia and mutism. The presentation of frontotemporal dementia may be confused with other dementias, including Alzheimer disease. It is important to distinguish between these different dementias because progression and patient management are different for the various dementias.

 

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive loss of upper and lower motor neurons. ALS typically presents with progressive muscle wasting, hyperreflexia, and spasticity. Death from respiratory failure usually occurs within 3 to 5 years of disease onset.

 

FTD and ALS are thought to represent a continuous disease spectrum. However, the molecular mechanism underlying the co-occurrence of FTD and ALS remains unclear. In some individuals ALS occurs first, while in others FTD precedes ALS by several years. Between 40% and 50% of individuals with ALS present with an FTD-associated clinical phenotype.

 

Given the clinical overlap of FTD and ALS, this multigene panel includes genes associated with FTD and ALS.

Reference Values

An interpretive report will be provided.

 

C9orf72 Repeats:

Normal alleles (reference): <20 GGGGCC repeats

Indeterminate alleles: 20-100 GGGGCC repeats

Pathogenic alleles:* >100 GGGGCC repeats

 

*The exact cutoff for pathogenicity is currently undefined. Although additional studies are needed to confirm if the cutoff for pathogenicity is 100 repeats, most individuals affected with a C9orf72-related disorder have C9orf72 hexanucleotide repeat expansions with hundreds to thousands of repeats.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

 

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See Targeted Genes and Methodology Details for Inherited Frontotemporal Dementia and Amyotrophic Lateral Sclerosis Gene Panel for details regarding the targeted genes analyzed for each test and specific gene regions not routinely covered.(Unpublished Mayo method)

 

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

 

A combined amplicon-length and repeat-primed PCR-based assay is utilized to size alleles up to approximately 145 repeats and detect expansions of GGGGCC hexanucleotide repeat region in the C9orf72 gene.(Ida CM, Lundquist PA, Bram E, et al. Evaluation of single-tube combined amplicon-length and repeat-primed long-read PCR assay for clinical detection and characterization of C9orf72 hexanucleotide repeat expansion. Abstract 731. 2017 ACMG Annual Clinical Genetics Meeting. Phoenix, AZ. March 23, 2017)

 

Genes analyzed: ALS2, ANG, ANXA11, APP, ASAH1, CCNF, CHCHD10, CHMP2B, CSF1R, DCTN1, ERBB4, FIG4, FUS, GRN, HEXB, HNRNPA1, HNRNPA2B1, ITM2B, KIF5A, MAPT, MATR3, NEFH, NOTCH3, NPC1, NPC2, OPTN, PANK2, PFN1, PRNP, PSEN1, PSEN2, SETX, SIGMAR1, SNCA, SOD1, SPG11, SPTLC1, SQSTM1, TAF15, TARDBP, TBK1, TBP, TIA1, TIMM8A, TREM2, TUBA4A, TYROBP, UBQLN2, VAPB, VCP, and VRK1.

Day(s) Performed

Varies

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

81403

81406 x 10

81404 x 3

81405 x 2

81407

81479

81479 (if appropriate for government payers)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
AFTDP FTD and ALS Gene Panel 51966-0

 

Result ID Test Result Name Result LOINC Value
617494 Test Description 62364-5
617495 Specimen 31208-2
617496 Source 31208-2
617497 Result Summary 50397-9
617498 Result 82939-0
617499 Interpretation 69047-9
618174 Additional Results 82939-0
617500 Resources 99622-3
617501 Additional Information 48767-8
617502 Method 85069-3
617503 Genes Analyzed 48018-6
617504 Disclaimer 62364-5
617505 Released By 18771-6

Testing Algorithm

For more information see Inherited Motor Neuron Disease and Dementia Testing Algorithm